HIV dementia (HIV-D) is one of the most common causes of dementia in young adults in the United States. Aberrant immune activation and oxidative stress within the central nervous system (CMS) play a significant role in the development of HIV-D. Disruptions in cytokine and redox balance produce reactive oxygen species which can attack proteins, deoxynucleic acids, and lipid membranes resulting in cellular dysfunction and cell death. Recent data from our group demonstrate increases in several markers of oxidative stress, specifically, ceramide, sphingomyelin, and 4-hydroxynonenal (HNE). The project will assemble a cohort of HIV+ individuals with varying degrees of neurocognitive impairment: 1) to define the association between markers of oxidative stress and HIV-D in a cohort of HAART-treated subjects and to determine the relationship between these markers and laboratory markers of macrophage and astrocyte activation and neuroimaging markers of inflammation and neuronal injury, 2) to determine whether markers of oxidative stress predict either the reversibility or the progression of HIV-D, and 3) to determine whether the antioxidant treatment, minocycline is safe in patients with HIV-D, improves HIV associated cognitive impairment, and decreases markers of oxidative stress. We propose the first large-scale prospective study to quantify novel markers of oxidative stress in individuals with HIV-associated cognitive impairment receiving HAART. This proposal examines the interrelationship between these markers and novel immune activation and neuroimaging markers of inflammation and neuronal injury to define the role of oxidative stress in the pathogenesis of HIV-D. This proposal will potentially identify new cellular targets of HIV-D treatment, and we will initiate a controlled clinical trial to test a new agent for the treatment of HIV-D. We believe that oxidative stress plays a significant role in the development of HIV-D, and strategies to decrease oxidative stress may serve as a useful therapeutic target to treat HIV-D.